Cancer cells have been likened to speeding cars. Mutated oncogenes hold down accelerator pedals; mutated tumor suppressor genes ruin brakes. Though often helpful, this analogy completely fails in the fascinating case of familial paraganglioma (PGL). Amazingly, PGL is a neuroendocrine cancer caused by loss of succinate dehydrogenase in the tricarboxylic acid (TCA) cycle of central metabolism. This is equivalent to severely disabling the engine of a car! How can loss-of-function mutations in a metabolic enzyme possibly be oncogenic, and why only in neuroendocrine cells? These irresistible biochemical questions drive this proposal, and answers will have significance for cancer therapy far beyond PGL. The central hypothesis is that succinate accumulation due to loss of SDH triggers neuroendocrine cell transformation by epigenetic effects resulting from inhibition of at least three different 2-ketoglutarate- dependent dioxygenase enzymes that produce succinate as a byproduct. It is as if the speeding car of cancer loses control because the driver is intoxicated by fumes from a faulty engine! We hypothesize that dioxygenase inhibition alters gene expression by novel epigenetic effects including (i) inappropriate activation of Hypoxia Inducible Factor (HIF), (ii) accumulation of methylated histones, and (iii) depletion of genomic 5-hydroxymethylcytosine. The strategy is to characterize PGL tumors and mammalian cells lacking SDH function, and to develop a nematode model of PGL for drug screening in Caenorhabditis elegans. Aim 1 will seek evidence for dioxygenase inhibition in primary human PGL tumor samples. Aim 2 will explore dioxygenase inhibition in cultured human and mouse cells lacking SDH. Aim 3 will monitor PGL tumorigenesis in mice with conditional SDH disruption. Finally, Aim 4 will develop a C. elegans model of PGL to uncover new therapeutics.